WO2007118602A1 - Composés pour traiter une hypertension pulmonaire - Google Patents

Composés pour traiter une hypertension pulmonaire Download PDF

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Publication number
WO2007118602A1
WO2007118602A1 PCT/EP2007/002985 EP2007002985W WO2007118602A1 WO 2007118602 A1 WO2007118602 A1 WO 2007118602A1 EP 2007002985 W EP2007002985 W EP 2007002985W WO 2007118602 A1 WO2007118602 A1 WO 2007118602A1
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Prior art keywords
substituted
alkyl
optionally substituted
alkylamino
ring
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PCT/EP2007/002985
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English (en)
Inventor
Martina Klein
Peter Sandner
Reiner Frey
Bernd Riedl
Olaf Christensen
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Bayer Healthcare Ag
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Priority to US12/297,217 priority Critical patent/US8304406B2/en
Priority to EP07723926A priority patent/EP2010173A1/fr
Priority to JP2009505742A priority patent/JP2009533479A/ja
Priority to CA002648957A priority patent/CA2648957A1/fr
Publication of WO2007118602A1 publication Critical patent/WO2007118602A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A61P33/12—Schistosomicides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to pharmaceutical compositions and combinations for treating, preventing or managing pulmonary hypertension comprising small molecule heterocyclic pharmaceuticals, and more particularly, substituted pyridines and pyridazines optionally combined with at least one additional therapeutic agent.
  • Pulmonary hypertension refers to a disease characterized by sustained elevations of pulmonary artery pressure (L.J. Rubin, The New England Journal of Medicine, 1997, 336(2), 111). Current treatment of pulmonary hypertension depends on the stage and the mechanism of the disease.
  • Typical treatments for pulmonary hypertension include anticoagulation, oxygen supplementation, conventional vasodilator therapy, transplantation and surgical care.
  • Therapeutic agents presently used for the treatment of pulmonary hypertension include e.g. calcium channel blockers and pulmonary vasodilators
  • the present invention provides pharmaceutical compositions for treating, preventing or managing pulmonary hypertension comprising a compound of formula I and optionally at least one further therapeutic agent.
  • the present invention can be used e.g. by administering a compound of formula I and optionally a further therapeutic agent, pharmaceutically-acceptable salts thereof, and derivatives thereof, etc.
  • the present invention relates to the sum of three sets of chemical compounds, or pharmaceutically acceptable salts or prodrugs thereof, with each set overlapping the others in scope.
  • the generalized structural formula for the compounds in each of the three sets of compounds is the same, but it should be noted that the definitions of the several groups comprising the general structure in each set differ somewhat.
  • the defined sets of chemical compounds differ from each other, but overlap in their scopes.
  • the first set of compounds have the generalized structural formula
  • each T 2 independently represents N, CH, or CG 1 ;
  • T 3 represents S, O, CR 4 G 1 , C(R 4 ) 2 , or NR 3 .
  • G 1 is a substituent independently selected from the group consisting of -N(R 6 ) 2 ; -NR 3 COR 6 ; halogen; alkyl; cycloalkyl; lower alkenyl; lower cycloalkenyl; halogen- substituted alkyl; amino-substituted alkyl; N-lower alkylamino-substituted alkyl; N,N-di-lower alkylamino-substituted alkyl; N-lower alkanoylamino-substituted alkyl; hydroxy-substituted alkyl; cyano-substituted alkyl; carboxy-substituted alkyl; lower alkoxycarbonyl-substituted alkyl; phenyl lower alkoxycarbonyl-substituted alkyl; halogen-substituted alkylamino; amino-substituted alkyl; N-low
  • R 3 is H or lower alkyl.
  • R 6 is independently selected from the group consisting of H; alkyl; cycloalkyl; optionally substituted aryl; optionally substituted aryl lower alkyl, lower alkyl- N(R 3 ) 2 , and lower alkyl-OH.
  • R 4 is H, halogen, or lower alkyl.
  • the subscript p is O, 1, or 2; and X is selected from the group consisting of O, S, and NR 3 .
  • the linking moiety Y is selected from the group consisting of lower alkylene; -CH 2 -O- ; -CH 2 -S- ; -CH 2 -NH- ; -O- ; -S- ; -NH- ; -0-CH 2 - ; -S(O)- ; -S(O) 2 - ; -SCH 2 - ; -S(O)CH 2 - ; -S(O) 2 CH 2 - ; -CH 2 S(O)- ; -CH 2 S(O) 2 ; -(CR 4 2 ) n -S(O) p -(5-membered heteroaryl)-(CR 4 2 ) s -; and -(CR 4 2 ) n -C(G 2 )(R 4 )- (CR 4 2 ) S - .
  • the substituent G 2 is selected from the group consisting of -CN, -CO 2 R 3 , -CON(R 6 ) 2 , and -CH 2 N(R 6 ) 2 .
  • Z represents CR 4 or N.
  • the number of possible substituents G 3 on the ring is indicated by subscript q, which is O, 1, or 2.
  • Substituent moieties G 3 are monovalent or bivalent moieties selected from the group consisting of: lower alkyl; -NR 3 COR 6 ; carboxy-substituted alkyl; lower alkoxycarbonyl-substituted alkyl; -OR 6 ;
  • -CN optionally substituted aryl; optionally substituted heteroaryl; optionally substituted saturated heterocyclyl; optionally substituted partially unsaturated heterocyclyl; optionally substituted heteroarylalkyl; optionally substituted heteroaryloxy; -S(O) p (optionally substituted heteroaryl); optionally substituted heteroarylalkyloxy; -S(O) p (optionally substituted heteroarylalkyl);
  • each T 2 independently represents N, CH, or CG 3' ; and T 3 represents S, O, CR 4 G 3' ,
  • G 3 represents any of the above-defined moieties G 3 which are monovalent; and the terminal T 2 of the bridge is bound to L, and T 3 is bound to D, thus forming a 5-membered fused ring.
  • a and D independently represent N or CH; B and E independently represent N or CH; and L represents N or CH; with the provisos - A -
  • J is a ring selected from the group consisting of aryl; pyridyl; and cycloalkyl.
  • the subscript q' represents the number of substituents G 4 on ring J and is 0, 1, 2, 3, 4, or 5.
  • the possible substituents G 4 on ring J are monovalent or bivalent moieties selected from the group consisting of -N(R 6 ) 2 ; -NR 3 COR 6 ; halogen; alkyl; cycloalkyl; lower alkenyl; lower cycloalkenyl; halogen-substituted alkyl; amino-substituted alkyl; N-lower alkylamino-substituted alkyl; N,N-di- lower alkylamino-substituted alkyl; N-lower alkanoylamino-substituted alkyl; hydroxy-substituted alkyl; cyano-substituted alkyl; carboxy-substituted alkyl; lower alkoxycarbonyl-substituted alkyl; phenyl lower alkoxycarbonyl-substituted alkyl; halogen-substituted alkylamino;
  • each T 2 independently represents N, CH, or CG 4 ;
  • T 3 represents S, O, CR 4 G 4' , C(R 4 ) 2 , or NR 3 ;
  • G4' represents any of the above-defined moieties G 4 which are monovalent; and binding to ring J is achieved via terminal atoms T 2 and T 3 ;
  • each T 2 independently represents N, CH, or CG 4 ;
  • G4' represents any of the above-defined moieties G 4 which are monovalent; with the proviso that a maximum of two bridge atoms T 2 may be N ; and binding to ring J is achieved via terminal atoms T 2 ;
  • each T 4 , T 5 , and T 6 independently represents O, S, CR 4 G 4' , C(R 4 ) 2 , or NR 3 ;
  • G4' represents any of the above-defined moieties G 4 which are monovalent; and binding to ring J is achieved via terminal atoms T 4 or T 5 ; with the provisos that:
  • T 4 when one T 4 is O, S, or NR 3 , the other T 4 is CR 4 G 4' or C(R 4 ) 2 ;
  • a bridge comprising T 5 and T 6 atoms may contain a maximum of two heteroatoms O, S, or N;
  • a bridge comprising T 5 and T 6 atoms, when one T 5 group and one T 6 group are O atoms, or two T 6 groups are O atoms, said O atoms are separated by at least one carbon atom.
  • G 4 is an alkyl group located on ring J adjacent to the linkage -(CR 4 2 ) P - , and X is NR 3 wherein R 3 is an alkyl substituent
  • G 4 and the alkyl substituent R 3 on X may be joined to form a bridge of structure -(CH 2 ) P' - wherein p' is 2, 3, or 4, with the proviso that the sum of p and p' is 2, 3, or 4, resulting in formation of a nitrogen-containing ring of 5, 6, or 7 members.
  • Additional provisos are that: 1) in G 1 , G 2 , G 3 , and G 4 , when two groups R 3 or R 6 are each alkyl and located on the same N atom they may be linked by a bond, an O, an S, or NR 3 to form a N- containing heterocycle of 5 - 7 ring atoms; and 2) when an aryl, heteroaryl, or heterocyclyl ring is optionally substituted, that ring may bear up to 5 substituents which are independently selected from the group consisting of amino, mono-loweralkyl-substituted amino, di-loweralkyl-substituted amino, lower alkanoylamino, halogeno, lower alkyl, halogenated lower alkyl, hydroxy, lower alkoxy, lower alkylthio, halogenated lower alkoxy, halogenated lower alkylthio, lower alkanoyl- oxy, -CO 2 R 3 , -CHO, -CH
  • the second set of compounds have the generalized structural formula
  • i) independently represent H or lower alkyl
  • binding is achieved via the terminal carbon atoms
  • one or two ring members T 1 are N and the others are CH or CG 1 , and binding is achieved via the terminal atoms;
  • each T 2 independently represents N, CH, or CG 1 ;
  • T 3 represents S, O, CR 4 G 1 , C(R 4 ) 2 , or NR 3 .
  • the subscript m is 0 or an integer 1 - 4; indicating that the resultant fused rings may optionally bear up to four substituents G 1 .
  • G 1 is a substituent independently selected from the group consisting of -N(R 6 ) 2 ; -NR 3 COR 6 ; halogen; alkyl; cycloalkyl; lower alkenyl; lower cycloalkenyl; halogen-substituted alkyl; amino- substituted alkyl; N-lower alkylamino-substituted alkyl; N,N-di-lower alkylamino-substituted alkyl; N-lower alkanoylamino-substituted alkyl; hydroxy-substituted alkyl; cyano-substituted alkyl; carboxy-substituted alkyl; lower alkoxycarbonyl-substituted alkyl; phenyl lower alkoxycarbonyl- substituted alkyl; halogen-substituted alkylamino; amino-substituted alkylamino; N-lower
  • R 3 is H or lower alkyl.
  • R 6 is independently selected from the group consisting of H; alkyl; cycloalkyl; optionally substituted aryl; optionally substituted aryl lower alkyl; lower alkyl- N(R 3 ) 2 , and lower alkyl-OH.
  • R 4 is H, halogen, or lower alkyl; the subscript p is O, 1, or 2; and X is selected from the group consisting of O, S, and NR 3 .
  • the linking moiety Y is selected from the group consisting of lower alkylene; -CH 2 -O- ; -CH 2 -S- ; -CH 2 -NH- ; -O- ; -S- ; -NH- ; -O-CH 2 - ; -S(O)- ; -S(O) 2 - ; -SCH 2 - ; -S(O)CH 2 - ; -S(O) 2 CH 2 - ; -CH 2 S(O)- ; -CH 2 S(O) 2 -; -(CR 4 2 ) n -S(O) p -(5-membered heteroaryl)-(CR 4 2 ) s -; and -(CR 4 2 ) n - C(G 2 )(R 4 )-(CR 4 2 ) S - .
  • G 2 is selected from the group consisting of -CN, -CO 2 R 3 , -CON(R 6 ) 2 , and -CH 2 N(R 6 ) 2 .
  • Z represents N or CR 4 .
  • the number of possible substituents G 3 on the ring is indicated by the subscript q, which is 1 or 2.
  • Substituents G 3 are monovalent or bivalent moieties selected from the group consisting of lower alkyl; -NR 3 COR 6 ; carboxy-substituted alkyl; lower alkoxycarbonyl-substituted alkyl; -OR 6 ; -SR 6 ; -S(O)R 6 ; -S(O) 2 R 6 ; -OCOR 6 ; -COR 6 ; -CO 2 R 6 ; -CH 2 OR 3 ; -CON(R 6 ) 2 ; -S(O) 2 N(R 6 ), ; -NO 2 ; -CN; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted saturated heterocyclyl; optionally substituted partially unsaturated heterocyclyl; optionally substituted heteroarylalkyl; optionally substituted heteroaryloxy; -S(O) p (optionally substituted heteroaryl); optionally substituted heteroarylalkyloxy;
  • each T 2 independently represents N, CH, or CG 3 ; and T 3 represents S, O, CR 4 G 3 , C(R 4 ) 2 , or NR 3 .
  • G 3 represents any of the above-defined moieties G 3 which are monovalent; and the terminal T 2 is bound to L, and T 3 is bound to D, thus forming a 5-membered fused ring.
  • J is a ring selected from the group consisting of aryl; pyridyl; and cycloalkyl.
  • the subscript q' represents the number of substituents G 4 on ring J and is 0, 1, 2, 3, 4, or 5.
  • G 4 is a monovalent or bivalent moiety selected from the group consisting of -N(R 6 ) 2 ; -NR 3 COR 6 ; halogen; alkyl; cycloalkyl; lower alkenyl; lower cycloalkenyl; halogen-substituted alkyl; amino- substituted alkyl; N-lower alkylamino-substituted alkyl; N,N-di-lower alkylamino-substituted alkyl; N-lower alkanoylamino-substituted alkyl; hydroxy-substituted alkyl; cyano-substituted alkyl; carboxy-substituted alkyl; lower alkoxycarbonyl-substituted alkyl; phenyl lower alkoxycarbonyl- substituted alkyl; halogen-substituted alkylamino; amino-substituted alkylamino;
  • each T 2 independently represents N, CH, or CG 4 ;
  • T 3 represents S, O, CR 4 G 4 , C(R 4 ) 2 , or NR 3 ;
  • G 4' represents any of the above-defined moieties G 4 which are monovalent; and binding to ring J is achieved via terminal atoms T 2 and T 3 ;
  • each T 2 independently represents N, CH, or CG 4 ;
  • G4 1 represents any of the above-defined moieties G 4 which are monovalent; with the proviso that a maximum of two bridge atoms T 2 may be N ; and binding to ring J is achieved via terminal atoms T 2 ;
  • each T 4 , T 5 , and T 6 independently represents O, S, CR 4 G 4' , C(R 4 ) 2 , or NR 3 ;
  • G4' represents any of the above-identified moieties G4 which are monovalent; and binding to ring J is achieved via terminal atoms T 4 or T 5 ; with the provisos that:
  • T 4 when one T 4 is O, S, or NR 3 , the other T 4 is CR 4 G 4' or C(R 4 ) 2 ;
  • a bridge comprising T 5 and T 6 atoms may contain a maximum of two heteroatoms O, S, or N;
  • a bridge comprising T 5 and T 6 atoms, when one T 5 group and one T 6 group are O atoms, or two T 6 groups are O atoms, said O atoms are separated by at least one carbon atom.
  • G 4 is an alkyl group located on ring J adjacent to the linkage -(CR 4 2 ) P - , and X is NR 3 wherein R 3 is an alkyl substituent
  • G 4 and the alkyl substituent R 3 on X may be joined to form a bridge of structure -(CH 2 ),, ' - wherein p 1 is 2, 3, or 4, with the proviso that the sum of p and p 1 is 2, 3, or 4, resulting in formation of a nitrogen-containing ring of 5, 6, or 7 members.
  • Additional provisos are that: 1) in G 1 , G 2 , G 3 , and G 4 , when two groups R 3 or R 6 are each alkyl and located on the same N atom they may be linked by a bond, an O, an S, or NR 3 to form a N- containing heterocycle of 5 - 7 ring atoms; and 2) when an aryl, heteroaryl, or heterocyclyl ring is optionally substituted, that ring may bear up to 5 substituents which are independently selected from the group consisting of amino, mono-loweralkyl-substituted amino, di-loweralkyl-substituted amino, lower alkanoylamino, halogeno, lower alkyl, halogenated lower alkyl, hydroxy, lower alkoxy, lower alkylthio, halogenated lower alkoxy, halogenated lower alkylthio, lower alkanoyloxy, -CO 2 R 3 , -CHO, -CH 2 OR
  • the third set of compounds have the generalized structural formula
  • i) independently represent H or lower alkyl
  • binding is achieved via the terminal carbon atoms
  • binding is achieved via the terminal carbon atoms
  • one or two ring members T 1 are N and the others are CH or CG 1 , and binding is achieved via the terminal atoms; or v) together form a bridge containing two T 2 moieties and one T 3 moiety, said bridge, taken together with the ring to which it is attached, forming a bicyclic of structure
  • each T 2 independently represents N, CH, or CG 1 ;
  • T 3 represents S, O, CR 4 G 1 , C(R 4 ) 2 , or NR 3 .
  • the subscript m is 0 or an integer 1 - 4; indicating that the resultant fused rings may optionally bear up to four substituents G 1 .
  • G 1 is a substituent independently selected from the group consisting of -N(R 5 ) 2 ; -NR 3 COR 6 ; halogen; alkyl; cycloalkyl; lower alkenyl; lower cycloalkenyl; halogen-substituted alkyl; amino- substituted alkyl; N-lower alkylamino-substituted alkyl; N,N-di-lower alkylamino-substituted alkyl; N-lower alkanoylamino-substituted alkyl; hydroxy-substituted alkyl; cyano-substituted alkyl; carboxy-substituted alkyl; lower alkoxycarbonyl-substituted alkyl; phenyl lower alkoxycarbonyl- substituted alkyl; halogen-substituted alkylamino; amino-substituted alkylamino; N-lower
  • R 3 is H or lower alkyl.
  • R 6 is independently selected from the group consisting of H; alkyl; cycloalkyl; optionally substituted aryl; optionally substituted aryl lower alkyl; lower alkyl- N(R 3 ) 2 , and lower alkyl-OH.
  • - B is independently selected from the group consisting of H; alkyl; cycloalkyl; optionally substituted aryl; optionally substituted aryl lower alkyl; lower alkyl- N(R 3 ) 2 , and lower alkyl-OH.
  • R 4 is H, halogen, or lower alkyl; the subscript p is 0, 1 , or 2; and X is selected from the group consisting of O, S, and NR 3 .
  • the linking moiety Y is selected from the group consisting of lower alkylene; -CH 2 -O- ; -CH 2 -S- ; -CH 2 -NH-; -O- ; -S-; -NH-; -0-CH 2 -; -S(O)-; -S(O) 2 -; -SCH 2 -; -S(O)CH 2 -; -S(O) 2 CH 2 -; -CH 2 S(O)-; -CH 2 S(O) 2 -; -(CR 4 2 ) n -S(OV(5-membered heteroaryl)-(CR 4 2 ) s -; and -(CR 4 2 ) n -C(G 2 )(R 4 )-(CR 4 2 ) s - .
  • G 2 is selected from the group consisting of -CN, -CO 2 R 3 , -CONOR 6 ⁇ , and -CH 2 N(R 6 ) 2 .
  • Z represents CR 4 .
  • the number of possible substituents G 3 on the ring is indicated by the subscript q, which is 1 or 2.
  • Substituents G 3 are monovalent or bivalent moieties selected from the group consisting of
  • each T 2 independently represents N, CH, or CG 3 ; and T 3 represents S, O, CR 4 G 3 , C(R 4 ) 2 , or NR 3 .
  • G 3 represents any of the above-defined moieties G 3 which are monovalent; and the terminal T 2 is bound to L, and T 3 is bound to D, thus forming a 5-membered fused ring.
  • J is a ring selected from the group consisting of aryl; pyridyl; and cycloalkyl.
  • the subscript q' represents the number of substituents G 4 on ring J and is O, 1, 2, 3, 4, or 5.
  • G 4 is a monovalent or bivalent moiety selected from the group consisting of -N(R 6 ) 2 ; -NR 3 COR 6 ;halogen; alkyl; cycloalkyl; lower alkenyl; lower cycloalkenyl; halogen-substituted alkyl; amino- substituted alkyl; N-lower alkylamino-substituted alkyl; N,N-di-lower alkylamino-substituted alkyl; N-lower alkanoylamino-substituted alkyl; hydroxy-substituted alkyl; cyano-substituted alkyl; carboxy-substituted alkyl; lower alkoxycarbonyl-substituted alkyl; phenyl lower alkoxycarbonyl- substituted alkyl; halogen-substituted alkylamino; amino-substituted alkylamino; N
  • each T 2 independently represents N, CH, or CG 4 ;
  • T 3 represents S, O,
  • G4' represents any of the above-defined moieties G4 which are monovalent; and binding to ring J is achieved via terminal atoms T 2 and
  • each T 2 independently represents N, CH, or CG 4 ;
  • G4 1 represents any of the above-defined moieties G4 which are monovalent; with the proviso that a maximum of two bridge atoms T 2 may be N ; and binding to ring J is achieved via terminal atoms T 2 ; and c)
  • each T 4 , T 5 , and T 6 independently represents O, S, CR 4 G 4 , C(R 4 ) 2 , or NR 3 ;
  • G4 1 represents any of the above-defined moieties G4 which are monovalent; and binding to ring J is achieved via terminal atoms T 4 or T 5 ; with the provisos that:
  • T 4 when one T 4 is O, S, or NR 3 , the other T 4 is CR 4 G 4' or C(R 4 ) 2 ;
  • a bridge comprising T 5 and T 6 atoms may contain a maximum of two heteroatoms O, S, or N;
  • a bridge comprising T 5 and T 6 atoms, when one T 5 group and one T 6 group are O atoms, or two T 6 groups are O atoms, said O atoms are separated by at least one carbon atom;
  • G 4 is an alkyl group located on ring J adjacent to the linkage -(CR 4 2 ) P -
  • X is NR 3 wherein R 3 is an alkyl substituent
  • G 4 and the alkyl substituent R 3 on X may be joined to form a bridge of structure -(CH 2 ) p .
  • p' is 2, 3, or 4, with the proviso that the sum of p and p 1 is 2, 3, or 4, resulting in formation of a nitrogen-containing ring of 5, 6, or 7 members.
  • Additional provisos are that: 1) in G 1 , G 2 , G 3 , and G 4 , when two groups R 3 or R 6 are each alkyl and located on the same N atom they may be linked by a bond, an O, an S, or NR 3 to form a N- containing heterocycle of 5 - 7 ring atoms; and 2) when an aryl, heteroaryl, or heterocyclyl ring is optionally substituted, that ring may bear up to 5 substituents which are independently selected from the group consisting of amino, mono-loweralkyl-substituted amino, di-loweralkyl-substituted amino, lower alkanoylamino, halogeno, lower alkyl, halogenated lower alkyl, hydroxy, lower alkoxy, lower alkylthio, halogenated lower alkoxy, halogenated lower alkylthio, lower alkanoyloxy, -CO 2 R 3 , -CHO, -CH 2 OR
  • the invention also relates to pharmaceutical compositions comprising one or more of the compounds of the invention, or their salts or prodrugs, in a pharmaceutically acceptable carrier.
  • the prefix “lower” denotes a radical having up to and including a maximum of 7 atoms, especially up to and including a maximum of 5 carbon atoms, the radicals in question being either linear or branched with single or multiple branching.
  • Alkyl means a hydrocarbon radical having up to a maximum of 12 carbon atoms, which may be linear or branched with single or multiple branching. Alkyl is especially lower alkyl.
  • Any asymmetric carbon atoms may be present in the (R)-, (S)- or (Reconfiguration, preferably in the (R)- or (S)-configuration.
  • the compounds may thus be present as mixtures of isomers or as pure isomers, preferably as enantiomer-pure diastereomers and having pure cis- or trans- double bonds.
  • Lower alkylene Y may be branched or linear but is preferably linear, especially methylene (-CH 2 ), ethylene (-CH 2 -CH 2 ), trimethylene (-CH 2 -CH 2 -CH 2 ) or tetramethylene (-CH 2 CH 2 CH 2 CH 2 ).
  • Y is lower alkylene, it is most preferably methylene.
  • Aryl means an aromatic radical having 6 to 14 carbon atoms, such as phenyl, naphthyl, fluorenyl or phenanthrenyl.
  • Halogen means fluorine, chlorine, bromine, or iodine but is especially fluorine, chlorine, or bromine.
  • Patentyl means 1-, 2-, or 3-pyridyl but is especially 2- or 3-pyridyl.
  • Cycloalkyl is a saturated carbocycle that contains between 3 and 12 carbons but preferably 3 to 8 carbons.
  • Cycloalkenyl means a non-reactive and non-aromatic unsaturated carbocycle that contains between 3 and 12 carbons but preferably 3 to 8 carbons and up to three double bonds. It is well known to those skilled in the art that cycloalkenyl groups that differ from aromatics by lacking only one double bond such as cyclohaxadiene are not sufficiently non-reactive to be reasonable drug substances and therefor their use as substituents is not within the scope of this invention.
  • Cycloalkyl and cycloalkenyl groups may contain branch points such that they are substituted by alkyl or alkenyl groups. Examples of such branched cyclic groups are 3,4-dimethylcyclopentyl, 4- allylcyclohexyl or 3-ethylcyclopent-3-enyl.
  • Salts are especially the pharmaceutically acceptable salts of compounds of formula I such as, for example, acid addition salts, preferably with organic or inorganic acids, from compounds of formula I with a basic nitrogen atom.
  • Suitable inorganic acids are, for example, halogen acids such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic, or sulfamic acids, for example acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, -hydroxybutyric acid, gluconic acid, glucosemonocarboxylic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azeiaic acid, malic acid, tartaric acid, citric acid, glucaric acid, galactaric acid, amino acids, such as glutamic acid, aspartic acid, N-methylglycine, acetytaminoacetic acid, N- acetylasparagine or N-acetylcysteine, pyruvic acid, acetoacetic acid, phosphoserine, 2- or 3- glycerophosphoric acid.
  • acetic acid propionic acid
  • the diradical "-(5 member heteroaryl)-" denotes a 5-membered aromatic heterocycle containing 1-3 heteroatoms selected from O, S, and N, the number of N atoms being 0- 3 and the number of O and S atoms each being 0-1 and connected to the sulfur from a carbon and to -(CR 4 2 ) S - through a C or N atom.
  • diradicals include
  • Heterocyclyl or “heterocycle” means a five- to seven-membered heterocyclic system with 1-3 heteroatoms selected from the group nitrogen, oxygen, and sulfur, which may be unsaturated or wholly or partly saturated, and is unsubstituted or substituted especially by lower alkyl, such as methyl, ethyl, 1 -propyl, 2-propyl, or tert-butyl.
  • ring may bear up to 5 substituents which are independently selected from the group consisting of amino, mono- or di-loweralkyl-substituted amino, lower alkanoylamino, halogeno, lower alkyl, halo- genated lower alkyl such as trifluoromethyl, hydroxy, lower alkoxy, lower alkylthio, halogenated lower alkoxy such as trifluoromethoxy, halogenated lower alkylthio such as trifluoromethylthio, lower alkanoyloxy, -CO 2 R 3 , -CHO, -CH 2 OR 3 , -OCO 2 R 3 , -CON(R 6 ) 2 , -OCO N(R 6 ) 2 , -NR 3 CON(R 6 ) 2 , nitro, amidino, guanidino, mercapto, sulfo,
  • the ring members A, B, D, E, and L may be N or CH, it being understood that the optional substituents G 3 are necessarily attached to carbon and not nitrogen, and that when a given carbon bears a substituent group G 3 , that G 3 group is in place of the H atom the carbon would bear in the absence of the G 3 group.
  • Heteroaryl means a monocyclic or fused bicyclic aromatic system with between 5 and 10 atoms in total of which 1-4 are heteroatoms selected from the group comprising nitrogen, oxygen, and sulfur and with the remainder being carbon. Heteroaryl is preferably a monocyclic system with 5 or 6 atoms in total, of which 1-3 are heteroatoms.
  • Alkenyl means an unsaturated radical having up to a maximum of 12 carbon atoms and may be linear or branched with single or multiple branching and containing up to 3 double bonds. Alkenyl is especially lower alkenyl with up to 2 double bonds.
  • Alkanoyl means alkylcarbonyl, and is especially lower alkylcarbonyl.
  • Halogenated lower alkyl, halogenated lower alkoxy and halogenated lower alkylthio are substituents in which the alkyl moieties are substituted either partially or in full with halogens, preferably with chlorine and/or fluorine and most preferably with fluorine.
  • substituents are trifiuoromethyl, trifiuoromethoxy, trifluoromethylthio, 1,1,2,2-tetrafluoroethoxy, dichloromethyl, fluoromethyl and difluoromethyl.
  • phenyl-lower alkoxycarbonyl- substituted alkylamino When a substituent is named as a string of fragments such as "phenyl-lower alkoxycarbonyl- substituted alkylamino," it is understood that the point of attachment is to the final moiety of that string (in this case amino) and that the other fragments of that string are connected to each other in sequence as they are listed in the string.
  • phenyl-lower alkoxycarbonyl- substituted alkylamino is: phenyl lower alkoxy alkyl
  • a substituent is named as a string of fragments with a bond at the start (typically written as a dash) such as "-S(O) p (optionally substituted heteroarylalkyl)", it is understood that the point of attachment is to the first atom of that string (in this case S or sulfur) and that the other fragments of that string are connected to each other in sequence as they are listed in the string.
  • -S(O) p optionally substituted heteroarylalkyl
  • R 1 and R 2 preferably:
  • binding is achieved via the terminal carbon atoms
  • one of the ring members T 1 is N and the others are CH, and binding is achieved via the terminal atoms;
  • each T 2 independently represents N, CH, or CG 1 ;
  • T 3 represents S, O, CH 2 , or NR 3 ;
  • T 3 is O or S, at least one T 2 is CH or CG 1 .
  • any group G 1 is located on a non-terminal atom of the bridge.
  • the terminal T 2 is N or CH
  • the non-terminal T 2 is CH or CG 1
  • T 3 is S or O.
  • substituents G 1 are preferably selected from the group consisting of -N(R 6 ) 2 ; -NR 3 COR 6 ; halogen; lower alkyl; hydroxy-substituted alkyl; amino-substituted alkylamino; N-lower alkylamino-substituted alkylamino; N,N-di-lower alkylamino-substituted alkylamino; hydroxy-substituted alkylamino; carboxy-substituted alkylamino; lower alkoxycarbonyl-substituted alkylamino; -OR 6 ; -SR 6 ; -S(O)R 6 ; -S(O) 2 R 6 ; halogenated lower alkoxy; halogenated lower alkylthio; halogenated lower alkylsulfonyl; -OCOR 6 ;
  • G 1 is a substituent independently selected from the group consisting of -N(R 6 ) 2 ; -NR 3 COR 6 ; halogen; -OR 6 wherein R6 represents lower alkyl; -NO 2 ; optionally substituted heteroaryloxy; and optionally substituted hetero- arylalkyloxy.
  • R 6 is an alkyl group, it is preferably lower alkyl.
  • the group R 4 is preferably H; p is preferably 0 or 1; and X is preferably NR 3 .
  • Y is selected from the group consisting of lower alkylene, -CH 2 -O-; -CH 2 -S-; -CH 2 -NH-; -S-; -NH-; -(CR 4 2 ) n -S(O) p -(5-membered heteroaryl)-(CR 4 2 ) s -; -(CR 4 2 ) n -C(G 2 )(R 4 )-(CR 4 2 ) s -; and -0-CH 2 -.
  • Y is selected from the group consisting of -CH 2 -O-; -CH 2 -NH-; -S-; -NH-; -(CR 4 2 ) n - S(O) p -(5-membered heteroaryl)-(CR 4 2 ) s - ; and -0-CH 2 -.
  • A, D, B, and E are preferably CH, and L is N or CH, with the proviso that when L is N, any substituents G 3 are preferably monovalent, and when L is CH then any substituents G 3 are preferably divalent.
  • T 3 is preferably S, O, CR 4 2 , or NR 3 .
  • the subscript q which represents the number of substituents G 3 , is 1.
  • Ring J is preferably a phenyl ring, and subscript q' representing the number of substituents G 4 on the phenyl ring, is preferably O, 1, 2, or 3. Subscript q' is most preferably 1, or 2.
  • G 4 moieties are preferably selected from the group consisting of -N(R 6 ) 2 ; -NR 3 COR 6 ; halogen; alkyl; halogen-substituted alkyl; hydroxy-substituted alkyl; carboxy-substituted alkyl; lower alkoxycarbonyl-substituted alkyl; amino-substituted alkylamino; N-lower alkylamino-substituted alkylamino; N,N-di-lower alkylamino-substituted alkylamino; N-lower alkanoylamino-substituted alkylamino; hydroxy-substituted alkylamino; carboxy-substituted alkylamino; lower alkoxy- carbonyl-substituted alkylamino; phenyl-lower alkoxycarbonyl-substituted alkylamino;
  • each T 2 independently represents N, or CH; T 3 represents S, or O; and binding to the phenyl ring is achieved via terminal atoms T 2 and T 3 ;
  • each T 2 independently represents N, CH, or CG 4 ; with the proviso that a maximum of two bridge atoms T 2 may be N ; and binding to the phenyl ring is achieved via terminal atoms T 2 ;
  • each T 5 , and T 6 independently represents O, S, or CH 2 ; and binding to ring J is achieved via terminal atoms T 5 ; with the provisos that: i) a bridge comprising T 5 and T 6 atoms may contain a maximum of two heteroatoms O, S, or N; and
  • a bridge comprising T 5 and T 6 atoms, when one T 5 group and one T 6 group are O atoms, or two T 6 groups are O atoms, said O atoms are separated by at least one carbon atom.
  • Alkyl groups which constitute all or part of a G 4 moiety are preferably lower alkyl.
  • G 4 is an alkyl group located on ring J adjacent to the linkage -(CR 4 2 ) P - , and X is NR 3 wherein R 3 is an alkyl substituent
  • G 4 and the alkyl substituent R 3 on X may be joined to form a bridge of structure -(CH 2 ) P - - wherein p' is preferably 2 or 3, with the proviso that the sum of p and p' is 2 or 3, resulting in formation of a nitrogen-containing ring of 5 or 6 members.
  • the sum of p and p 1 is 2, resulting in formation of a 5-membered ring.
  • G 1 , G 2 , G 3 , and G 4 when two groups R 6 are each alkyl and located on the same N atom they may be linked by a bond, an O, an S, or NR 3 to form a N-containing heterocycle of 5 — 6 ring atoms.
  • aryl, heteroaryl, or heterocyclyl ring when an aryl, heteroaryl, or heterocyclyl ring is optionally substituted, that ring may bear up to 2 substituents which are independently selected from the group consisting of amino, mono-loweralkyl-substituted amino, di-loweralkyl-substituted amino, lower alkanoylamino, halo- geno, lower alkyl, halogenated lower alkyl, hydroxy, lower alkoxy, lower alkylthio, halogenated lower alkoxy, halogenated lower alkylthio, -CH 2 OR 3 , nitro, and cyano.
  • substituents which are independently selected from the group consisting of amino, mono-loweralkyl-substituted amino, di-loweralkyl-substituted amino, lower alkanoylamino, halo- geno, lower alkyl, halogenated lower alkyl, hydroxy,
  • the method of the invention is intended to be employed for treatment of VEGF-mediated conditions in both humans and other mammals.
  • the compounds may be administered orally, dermally, parenterally, by injection, by inhalation or spray, or sublingually, rectally or vaginally in dosage unit formulations.
  • the term 'administered by injection' includes intravenous, intraarticular, intramuscular, subcutaneous and parenteral injections, as well as use of infusion techniques.
  • Dermal administration may include topical application or transdermal administration.
  • One or more compounds may be present in association with one or more non-toxic pharmaceutically acceptable carriers and if desired, other active ingredients.
  • compositions intended for oral use may be prepared according to any suitable method known to the art for the manufacture of pharmaceutical compositions.
  • Such compositions may contain one or more agents selected from the group consisting of diluents, sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; and binding agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. These compounds may also be prepared in solid, rapidly released form.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions containing the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions may also be used.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbit
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or ⁇ -propyl, /7-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or ⁇ -propyl, /7-hydroxybenzoate
  • coloring agents for example ethyl, or ⁇ -propyl, /7-hydroxybenzoate
  • coloring agents for example ethyl, or ⁇ -propyl, /7-hydroxybenzoate
  • flavoring agents for example ethyl, or ⁇ -propyl, /7-hydroxybenzoate
  • sweetening agents such as sucrose or saccharin.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.
  • the compounds may also be in the form of non-aqueous liquid formulations, e.g., oily suspensions which may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or peanut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • a thickening agent for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations.
  • These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oil phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the compounds may also be administered in the form of suppositories for rectal or vaginal administration of the drug.
  • suppositories for rectal or vaginal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug.
  • Such materials include cocoa butter and polyethylene glycols.
  • Compounds of the invention may also be administered transdermally using methods known to those skilled in the art (see, for example: Chien; “Transdermal Controlled Systemic Medications”; Marcel Dekker, Inc.; 1987. Lipp et al. WO 94/04157 3Mar94).
  • a solution or suspension of a compound of Formula I in a suitable volatile solvent optionally containing penetration enhancing agents can be combined with additional additives known to those skilled in the art, such as matrix materials and bactericides. After sterilization, the resulting mixture can be formulated following known procedures into dosage forms.
  • a solution or suspension of a compound of Formula I may be formulated into a lotion or salve.
  • Suitable solvents for processing transdermal delivery systems are known to those skilled in the art, and include lower alcohols such as ethanol or isopropyl alcohol, lower ketones such as acetone, lower carboxylic acid esters such as ethyl acetate, polar ethers such as tetrahydrofuran, lower hydrocarbons such as hexane, cyclohexane or benzene, or halogenated hydrocarbons such as dichloromethane, chloroform, trichlorotrifluoroethane, or trichlorofluoroethane.
  • Suitable solvents may also include mixtures one or more materials selected from lower alcohols, lower ketones, lower carboxylic acid esters, polar ethers, lower hydrocarbons, halogenated hydrocarbons.
  • Suitable penetration enhancing materials for transdermal delivery systems include, for example, monohydroxy or polyhydroxy alcohols such as ethanol, propylene glycol or benzyl alcohol, saturated or unsaturated C 8 -Q 8 fatty alcohols such as lauryl alcohol or cetyl alcohol, saturated or unsaturated Cg-C] 8 fatty acids such as stearic acid, saturated or unsaturated fatty esters with up to 24 carbons such as methyl, ethyl, propyl, isopropyl, «-butyl, sec-butyl isobutyl tert-buty ⁇ or monoglycerin esters of acetic acid, capronic acid, lauric acid, myristinic acid, stearic acid, or palmitic acid, or diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons such as diisopropyl adipate, diisobutyl adipate, diisopropy
  • Additional penetration enhancing materials include phosphatidyl derivatives such as lecithin or cephalin, terpenes, amides, ketones, ureas and their derivatives, and ethers such as dimethyl isosorbid and diethyleneglycol monoethyl ether.
  • Suitable penetration enhancing formulations may also include mixtures one or more materials selected from monohydroxy or polyhydroxy alcohols, saturated or unsaturated C 8 -Ci 8 fatty alcohols, saturated or unsaturated C 8 -Ci 8 fatty acids, saturated or unsaturated fatty esters with up to 24 carbons, diesters of saturated or unsaturated dicarboxylic acids with a total of up to 24 carbons, phosphatidyl derivatives, terpenes, amides, ketones, ureas and their derivatives, and ethers.
  • Suitable binding materials for transdermal delivery systems include polyacrylates, silicones, polyurethanes, block polymers, styrene-butadiene coploymers, and natural and synthetic rubbers.
  • Cellulose ethers, derivatized polyethylenes, and silicates may also be used as matrix components. Additional additives, such as viscous resins or oils may be added to increase the viscosity of the matrix.
  • the daily oral dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight.
  • the daily dosage for administration by injection including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/Kg of total body weight.
  • the daily rectal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight.
  • the daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/Kg of total body weight.
  • the daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/Kg.
  • the daily inhalation dosage regimen will preferably be from 0.01 to 10 mg/Kg of total body weight.
  • the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be understood, however, that the specific dose level for any given patient will depend upon a variety of factors, including, but not limited to the activity of the specific compound employed, the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, drug combinations, and the severity of the condition undergoing therapy.
  • the optimal course of treatment i.e., the mode of treatment and the daily number of doses of a compound of Formula I or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.
  • the compounds of the invention may be prepared by use of known chemical reactions and procedures. Nevertheless, the following general preparative methods are presented to aid the reader in synthesizing the KDR inhibitors, with more detailed particular examples being presented below in the experimental section describing the working examples.
  • variable groups of these methods are as described in the generic description if they are not specifically defined below.
  • a variable group or substituent with a given symbol i.e. R 3 , R 4 , R 6 , G 1 , G 2 , G 3 , or G 4
  • each of these groups or substituents may be independently varied within the range of definitions for that symbol.
  • the compounds of the invention contain ring units each of which may independently bear between 0 and 5 substituents G 1 , G 3 , or G 4 , which are not defined as H.
  • G 1 , G 3 , or G 4 substituents are used as if their definition includes H, to show where such G 1 , G 3 , or G 4 substituents may exist in the structures, and for ease in drawing. No change in the definition of G 1 , G 3 , or G 4 is intended by this non-standard usage, however.
  • G 1 , G 3 , or G 4 may be H in addition to the moieties set forth in the definitions of G 1 , G 3 , or G 4 .
  • the ultimate compounds contain 0 to 5 non-hydrogen groups G 1 , G 3 , or G 4 .
  • variable M is equivalent to the moiety in which each va ⁇ able group or substit ⁇ ent is allowed to independently vary within the limits defined earlier for that symbol.
  • va ⁇ able Q 1 is equivalent to the moiety
  • va ⁇ able Q 2 is equivalent to the moiety
  • a heterocycle of formula IT in which R is lower alkyl can be made by one skilled m the art according to the corresponding published procedures in the reference table
  • the carboxyhc acids are converted to methyl or ethyl esters by treatment with the corresponding alcohol and catalytic mineral acid (typically sulfu ⁇ c acid) at reflux.
  • the diester of formula FT is treated with hydrazine hydrate to furnish intermediate III (for specific reaction conditions see Robba, M., Le Guen, Y. Bull Soc Chem Fr 1970 12 4317).
  • Compound III is treated with a halogenatmg agent such as phosphorous oxychlo ⁇ de, phosphorous oxybromide, phosphorous pentabromide, or phosphorous pentachlo ⁇ de to yield dihalo intermediate IV.
  • a halogenatmg agent such as phosphorous oxychlo ⁇ de, phosphorous oxybromide, phosphorous pentabromide, or phosphorous pentachlo ⁇ de
  • the dichloro or dibromo intermediates can be converted to the difluoro intermediate (when desired) by reaction with hydrogen fluoride.
  • iodo reagents such as potassium iodide or tetrabutyl- ammonium iodide in subsequent steps, the iodo intermediate is formed in the reaction mixtures without being isolated as a pure substance.
  • Dihalo intermediate IV is treated with a nucleophile of formula V in refluxing alcohol or other suitable solvent such as tetrahydrofuran (THF), dimethoxyethane (DME), dimethylformamide (DMF), dimethylsulfoxide (DMSO), or the like to furnish the intermediate of formula VI.
  • suitable solvent such as tetrahydrofuran (THF), dimethoxyethane (DME), dimethylformamide (DMF), dimethylsulfoxide (DMSO), or the like.
  • THF tetrahydrofuran
  • DME dimethoxyethane
  • DMF dimethylformamide
  • DMSO dimethylsulfoxide
  • condensations can also be done in a melt free of solvent and can be catalyzed by acids such as HCl or bases such as triethylamine or 1,8- diazobicyclo[5.4.0]undec-7-ene (DBU).
  • the compound of formula VI is reacted with compounds of formula VII in a suitable aprotic solvent such as DMSO, DMF or solvent free often with a basic catalyst such as DBU or CsCO 4 , or a crown ether such as 18-crown-6 at temperatures usually between room temperature and reflux to furnish invention compound of formula I-A.
  • a suitable aprotic solvent such as DMSO, DMF or solvent free often with a basic catalyst such as DBU or CsCO 4 , or a crown ether such as 18-crown-6 at temperatures usually between room temperature and reflux
  • a suitable aprotic solvent such as DMSO, DMF or solvent free often with a basic catalyst such as DBU or CsCO 4 , or a crown ether such as 18-crown-6 at temperatures usually between room temperature and reflux
  • a basic catalyst such as DBU or CsCO 4
  • a crown ether such as 18-crown-6
  • condensations can also be done in a melt free of solvent and can be catalyzed by acids such as HCl or bases such as triethylamine or 1,8- diazobicyclo[5.4.0]undec-7-ene (DBU).
  • acids such as HCl or bases
  • bases such as triethylamine or 1,8- diazobicyclo[5.4.0]undec-7-ene (DBU).
  • DBU 1,8- diazobicyclo[5.4.0]undec-7-ene
  • condensations can also be done in a melt free of solvent and can be catalyzed by acids such as HCl or bases such as triethylamine or 1,8- diazobicyclo[5.4.0]undec-7-ene (DBU).
  • acids such as HCl or bases
  • bases such as triethylamine or 1,8- diazobicyclo[5.4.0]undec-7-ene (DBU).
  • reagent V can be condensed with intermediate XV be heating the two components with P 2 O 5 in a melt to yield invention compound of structure I-C. This last method is especially effective when X is an amine linker.
  • a suitable halogenating agent such as POCl 3 , POBr 3 , PCl 5 , PBr 5 or thionyl chloride yields a halo intermediate which is reacted with nucleophile of formula V in refluxing alcohol to furnish intermediate compound of formula XXIII.
  • a suitable halogenating agent such as POCl 3 , POBr 3 , PCl 5 , PBr 5 or thionyl chloride
  • reagent V can be condensed with intermediate XXII be heating the two components with P 2 O 5 in a melt to yield XXn.
  • This last method is especially effective when X is an amine linker.
  • Formation and alkylation of the Reissert compound XXTTT with halide XXTV is done as described by the general method of F.D. Popp, Heterocycles, 1980, 14, 1033 to yield the intermediate of structure XXV.
  • Treatment of XXV with base then yields invention compound I-F.
  • Reaction of XXXTV with either potassium or sodium hydrogen sulfide yields a thiol having formula XXXV.
  • the alcohol function of intermediate XXXII from method H is converted to a leaving group by reaction with methanesulfonyl chloride and a suitable base such as triethylamine in the cold such that polymeric material formation is minimized and the resultant intermediate is reacted with either potassium or sodium hydrogen sulfide to yield a thiol having formula XXXVI.
  • the expected side products consisting of mixtures of various N oxides and the sulfone I-J-2 can be removed by chromatography.
  • the sulfone I-J-2 is obtained by the use of an additional equivalent of MCPBA or preferably by use of potassium permanganate in acetic acid/water (Eur. J. Med. Chem. Ther., 21, 1, 5-8, 1986) or by use of hydrogen peroxide in acetic acid (Chem. Heterocycl. Compd., 15, 1085-1088, 1979).
  • the pyrazole starting material can be prepared by reacting 2-oxo-3-pentyn-l,5-dioic acid (J. Chem. Phys. 1974, 60, 1597) with diazomethane.
  • the starting material wherein R 1 and R 2 together with the carbons to which they are attached form a phenyl are prepared by the methods of Cymerman-Craig et al., Aust. J. Chem. 1956, P, 222, 225.
  • Pyridazinone XXXVHI is treated with a chlorinating agent such as phosphorous oxychloride to yield an intermediate dichloro species which undergoes hydrolysis upon aqueous workup to furnish chloropyridazine XXXIX.
  • Chloro acid XXXIX is treated with a nucleophile of formula V in the presence of a base such as sodium hydride in a solvent such as DMF or in the absence of a solvent.
  • the resultant acid XXXX is reduced with a reducing agent such as BH 3 -THF according to the procedure of Tilley, J. W.; Coffen D. L. Schaer, B. H.; Lind, J. J. Org. Chem. 1987 52 2469.
  • Product alcohol XXXXI is reacted with a base and optionally substituted 4-halo-pridyl, optionally substituted 4-halo-pyrimidyl or optionally substituted 4-halo- pyridazyl (XXXXII) to furnish invention compound of formula I-K (for specific reaction conditions see Barlow, J. J.; Block, M. H.; Hudson, J. A.; Leach, A.; Longridge, J. L.; Main, B. g.; Nicholson, S. J. Org. Chem. 1992 575158).
  • XXXXI is converted to halo intermediate of formula XXXXTV by methods well known to those skilled in the art and the halide is reacted with thiol XXXXV to yield I-K.
  • Intermediate XXXXrV can also be converted to intermediate XXXXm by treatment with KHS or NaHS.
  • Reagents XXXXV are either commercially available such as 4-mercaptopyridine or can be prepared by one skilled in the art such as by method I above.
  • the compounds of formula I according to the present invention can be combined with further therapeutic agents presently used to treat, prevent or manage pulmonary hypertension such as, but notlimited to, anticoagulants, diuretics, cardiac glycosides, calcium channel blockers, vasodilators, prostacyclin analogues, endothelium antagonists, phosphodiesterase inhibitors, endopeptidase inhibitors, lipid lowering agents, thromboxane inhibitors and other therapeutics known to reduce pulmonary artery pressure.
  • therapeutic agents presently used to treat, prevent or manage pulmonary hypertension such as, but notlimited to, anticoagulants, diuretics, cardiac glycosides, calcium channel blockers, vasodilators, prostacyclin analogues, endothelium antagonists, phosphodiesterase inhibitors, endopeptidase inhibitors, lipid lowering agents, thromboxane inhibitors and other therapeutics known to reduce pulmonary artery pressure.
  • anticoagulants include, but are not limited to, e.g. warfarin useful in the treatment of patients with pulmonary hypertension having an increased risk of thrombosis and thromboembolism.
  • calcium channel blockers include, but are not limited to, diltiazem, felodipine, amlodipine and nifedipine particularly useful for vasoreactive patients at right heart catheteri- zation.
  • vasodilators include, but are not limited to, e.g. prostacyclin, epoprostenol, treprostinil and nitric oxide (NO).
  • phosphodiesterase inhibitors include, but are not limited to, particularly phosphodiesterase V inhibitors such as e.g. tadalafil, sildenafil and vardenaf ⁇ l.
  • endothelin antagonists include, but are not limited to, e.g. bosentan and sitaxentan, preferably bosetan.
  • prostacyclin analogues include, but are not limited to, e.g. ilomedin, treprostinil and epoprostenol.
  • lipid lowering agents include, but are not limited to, e.g. HMG CoA reductase inhibitors such as simvastatin, pravastatin, atorvastatin, lovastatin, itavastatin, fluvastatin, pitavastatin, rosuvastatin, ZD-4522 and cerivastatin
  • diuretics include, but are not limited to, e.g. chlorthalidon, indapamid, bendro- flumethiazid, metolazon, cyclopenthiazid, polythiazid, mefrusid, ximapid, chlorothiazid and hydrochlorothiazid particularly useful to manage peripheral edema.
  • Examples of other therapeutics known to reduce pulmonary artery pressure include, but are not limited to, e.g. ACE inhibitors such as enalapril, ramipril, captopril, cilazapril, trandolapril, fosinopril, quinapril, moexipril, lisinopril and perindopril, or AT II inhibitors such as losartan, candesartan, irbesartan, embusartan, valsartan and telmisartan, or iloprost, betaprost, L-arginine, omapatrilat, oxygen particularly useful in those patients with resting or exercise-induced hypoxemia or digoxin particularly useful to improve right ventricular function in patients with right ventricular failure.
  • ACE inhibitors such as enalapril, ramipril, captopril, cilazapril, trandolapril, fosinopril, quinapri
  • kinase inhibitors include, but are not limited to, e.g. BMS-354825, canertinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, lonafarnib, pegaptanib, pelitinib, semaxanib, tandutinib, tipifarnib, vatalanib, lonidamine, fasudil, leflunomide, bortezomib, imatinib, erlotinib and glivec. Preference is given to glivec.
  • the compounds and combinations of the invention can be combined with NO- independent and heme-dependent guanylyl cyclase stimulators and/or NO- and heme- independent guanylyl cyclase activators.
  • NO-independent and heme-dependent guanylyl cyclase stimulators include, but are not limited to, e.g. compounds described in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451.
  • the compounds and combinations according to the present invention can be used for manufacture of a medicament for treating, preventing and managing pulmonary hypertension.
  • the present invention provides methods of treating, preventing and managing pulmonary hypertension, comprising administering effective amounts of at least one compound of formula I and optionally at least one further therapeutic agent according to the invention.
  • An "effective amount" is the quantity of the compound that is useful to achieve the desired result, e.g., to treat, prevent or manage the disease or condition.
  • pulmonary hypertension include, but is not limited to, primary pulmonary hypertension, secondary pulmonary hypertension, familial pulmonary hypertension, sporadic pulmonary hypertension, precapillary pulmonary hypertension, pulmonary arterial, pulmonary artery hypertension, idiopathic pulmonary hypertension, thrombotic pulmonary arteriopathy, plexogenic pulmonary arteriopathy and pulmonary hypertension associated with or related to, left ventricular dysfunction, mitral valvilar disease, constrictivepericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis, anomalous pulmonary venous drainage, pulmonary venoocclusive disease, collagen vascular disease, congenital heart disease, congenital heart disease, pulmonary venus hypertension, chronic obstructive pulmonary disease, interstitial lung disease, sleep-disordered breathing, alveolarhyperventilation disorder, chronic exposure to high altitude, neonatal lung disease, alveolar-capillary dysplasia,
  • Any form of pulmonary hypertension can be treated in accordance with the present invention, including, but not limited to, mild, e.g., associated with increases of mean blood pressure of about 20-30 mm Hg at rest; moderate, e.g., associated with increases of 30-39 mm Hg at rest; and severe, e.g., associated with increases of 40 mm Hg or more at rest.
  • Pulmonary hypertension includes pulmonary arterial hypertension (PAH), and includes, primary pulmonary hypertension (PPH), idiopathic PAH (IPAH), familial PAH (FPAH).
  • PPH primary pulmonary hypertension
  • IPAH idiopathic PAH
  • FPAH familial PAH
  • any of the above-mentioned disorders can be associated with an increased risk of pulmonary hypertension, including, subjects having, e.g., congenital heart disease (e.g., Eisenmenger syndrome); left heart disease; pulmonary venous disease (e.g., fibrosis tissue narrowing or occluding pulmonary veins and venules); pulmonary arterial disease; diseases causing alveolar hypoxia; fibrotic lung diseases; Williams syndrome; subjects with intravenous drug abuse injury; pulmonary vasculitis (such as Wegener's, Goodpasture's, and Churg-Strauss syndromes); emphysema; chronic bronchitis; kyphoscoliosis; cystic fibrosis; obesity-hyper-ventilation and sleep apnea disorders; pulmonary fibrosis; sarcoidosis; silocosis; CREST (calcinosis cutis, Raynaud phenomenon; esophageal motility disorder; scle
  • a subject who possesses a BMPR2 mutation has a 10-20% lifetime risk of acquiring FPAH.
  • Subjects with hereditary hemorrhagic telangiectasa were also identified as being at risk for IPAH, especially those carrying mutations in ALKl. See, McGoon et al., Chest, 2004, 126, 14-34.
  • the term “treating” refers to the administration of a pharmaceutical composition after the onset of symptoms of pulmonary hypertension, whereas "preventing” refers to the administration prior to the onset of symptoms, particularly to patients at risk of pulmonary hypertension.
  • the term “managing” encompasses preventing the recurrence of pulmonary hypertension in a patient who suffered from pulmonary hypertension.
  • Compounds or drug combinations of the present invention can be administered in any form by any effective route, including, e.g., oral, parenteral, enteral, intravenous, intraperitoneal, topical, transdermal (e.g., using any standard patch), ophthalmic, nasally, local, non-oral, such as aerosal, inhalation, subcutaneous, intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial, and intrathecal, etc. They can be administered alone, or in combination with any ingredient(s), active or inactive.
  • any effective route including, e.g., oral, parenteral, enteral, intravenous, intraperitoneal, topical, transdermal (e.g., using any standard patch), ophthalmic, nasally, local, non-oral, such as aerosal, inhalation, subcutaneous, intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial, and intrathecal, etc. They can be administered alone, or in
  • Compounds or drug combinations of the present invention can be converted in a known manner into the usual formulations, which may be liquid or solid formulations e.g. without limitation normal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solution, suspensions, syrups, solid and liquid aerosols and emulsions.
  • formulations which may be liquid or solid formulations e.g. without limitation normal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solution, suspensions, syrups, solid and liquid aerosols and emulsions.
  • the combinations of the present invention can be administered at any time and in any effective form.
  • the compounds can be administered simultaneously, e.g., as a single composition or dosage unit (e.g., a pill or liquid containing both compositions), or they can be administered as separate compositions, but at the same time (e.g., where one drug is administered intravenously and the other is administered orally or intramuscularly).
  • the drugs can also be administered sequentially at different times.
  • Agents can be formulated conventionally to achieve the desired rates of release over extended period of times, e.g., 12-hours, 24-hours. This can be achieved by using agents and/or their derivatives which have suitable metabolic half-lives, and/or by using controlled release formulations.
  • the drug combinations can be synergistic, e.g., where the joint action of the drugs is such that the combined effect is greater than the algebraic sum of their individual effects.
  • reduced amounts of the drugs can be administered, e.g., reducing toxicity or other deleterious or unwanted effects, and/or using the same amounts as used when the agents are administered alone, but achieving greater efficacy.
  • additives include any of the substances already mentioned, as well as any of those used conventionally, such as those described in Remington: The Science and Practice of Pharmacy (Gennaro and Gennaro, eds, 20th edition,
  • compounds or drug combinations of the present invention can be administered with other active agents or other therapies that are utilized to treat any of the above-mentioned diseases and/or conditions.
  • the present invention provides also combinations of at least one compound of Formula I and at least one other therapeutic agent mentioned above useful in treating a disease or disorder.
  • “Combinations” for the purposes of the invention include:
  • compositions or dosage forms which contain at least one compound of Formula I and at least one other therapeutic agent mentioned above;
  • kits which comprise at least one compound of Formula I and at least one other therapeutic agent mentioned above packaged separate from one another as unit dosages or as independent unit dosages, with or without instructions that they be administered concurrently or sequentially;
  • each agent of the combination can be selected with reference to the other and/or the type of disease and/or the disease status in order to provide the desired therapeutic activity.
  • the active agents in the combination can be present and administered in a fixed combination.
  • "Fixed combination” is intended here to mean pharmaceutical forms in which the components are present in a fixed ratio that provides the desired efficacy. These amounts can be determined routinely for a particular patient, where various parameters are utilized to select the appropriate dosage (e.g., type of disease, age of patient, disease status, patient health, weight, etc.), or the amounts can be relatively standard.
  • the amount of the administered active ingredient can vary widely according to such considerations as the particular compound and dosage unit employed, the mode and time of administration, the period of treatment, the age, sex, and general condition of the patient treated, the nature and extent of the condition treated, the rate of drug metabolism and excretion, the potential drug combinations and drug-drug interactions, and the like.
  • the compound of formula I is administered in combination with at least one further therapeutic agent in an amount that those of ordinary skill in the art can determine by their professional judgement.
  • the pharmaceutical composition according to the invention is administered one or more, preferably up to three, more preferably up to two times per day. Preference is given to an administration via the oral route. With each administration the number of tablets or capsules taken in at the same time should not exceed two.
  • the combination can comprise effective amounts of at least one compound of Formula I and at least one other therapeutic agent mentioned above, which achieves a greater therapeutic efficacy than when either compound is used alone.
  • the combination can be useful to treat, prevent or manage pulmonary hypertension, where the therapeutic effect is not observed when the agents are used alone, or where an enhanced effect is observed when the combination is administered.
  • the relative ratios of each compound in the combination can also be selected based on their respective mechanisms of action and the disease biology.
  • the relative ratios of each compound can vary widely and this invention includes combinations for treating, preventing or managing pulmonary hypertension where the amounts of the formula I compound and the other therapeutic agent can be adjusted routinely such that either is present in higher amounts.
  • the release of one or more agents of the combination can also be controlled, where appropriate, to provide the desired therapeutic activity when in a single dosage form, combination pack, kit or when in separate independent dosage forms.
  • Preference is given to a combination comprising a compound of formula I and at least one compound selected from the group consisting of phosphodiesterase V inhibitors, endothelin antagonists, prostacyclin analogues, kinase inhibitors and elastase inhibitors.
  • a combination comprising 4-(4-chlorophenylamino)-7-(2-aminocarbonyl-4-pyridylmethoxy)furo- [2,3-d]pyridazine and at least one compound selected from the group consisting of tadalaf ⁇ l, sildenafil, vardenafil, bosentan, sitaxentan, ilomedin, treprostinil and epoprostenol is used.
  • Step 3 A mixture of 0.05 g, 0.1498 mMol of l-(4-chloroaniline)-4-bromoisoquiniline and 0.02 g, O.l ⁇ mMol of 4-mercaptopyridine were combined and melted together at 140° for about 10 minutes.
  • the resulting reaction mixture was purified on a 1000 micron prep plate using 5% methanol in hexanes as the solvent, wt. 0.0103 g, 19% yield, mp. 192-195°.
  • R f 0.50 in 40% ethyl acetate in hexanes.
  • Example 1 The procedure used for the preparation of Example 1 was used to prepare the title compound by substituting 5-aminoindane for 4-chloroaniline in step 2. Mp. 100-103°, TLC R f 0.40 (40% ethyl acetate in hexanes).
  • Example 1 The procedure used for the preparation of Example 1 was used to prepare the title compound by substituting 6-aminobenzothiazole for 4-chloroaniline in step 2.
  • Step 1 A mixture of homophthalimide (770 mg, 4.78mmol), 4-pyridinecarboxaldehyde (0.469 mL, 4.78 mmol) and piperidine (0.5 mL) in acetic acid (25 mL) was heated at reflux for 1 h. The resultant solution was cooled to room temperature. The solid product was removed by filtration, washed by water (4 x 10 mL) and dried under vacuum to afford 920 mg (3.67 mmol, 77 % yield ) of a mixture of Z and E isomers of the above compound. 1 H-NMR (DMSO-de) complex proton signals shown in aromatic region due to existence of both E and Z isomers. MS ES 251 (M+H) + , 252 (M+2H) + .
  • Step 3 A mixture of 4-chloroaniline (178 mg, 1.40 mmol), phosphorus pentoxide (396 mg, 1.40 mmol) and triethylamine hydrochloride (193 mg, 1.40 mmol) was heated and stirred under argon at 200 0 C for 1.5 h or until a homogenous melt has formed. To the melt was added starting material (82 mg, 0.35 mmol). The reaction mixture was stirred at 200 OC for 2 h. The resultant solid black mass was cooled to 100 0 C. Methanol (5 mL) and water (10 mL) were added and the reaction mixture was sonicated until the black mass had become soluble.
  • Example 4 The procedure used for the preparation of Example 4 was used to prepare the title compound by substituting 6-aminobenzothiazole for 4-chloroaniline in step 3.
  • Example 6 Preparation of l-( indan-5-ylamino)-4-(4-pyridylmethyl)-isoquinoline
  • Example 4 The procedure used for the preparation of Example 4 was used to prepare the title compound by substituting 5-aminoindane for 4-chloroaniline in step 3.
  • Example 4 The procedure used for the preparation of Example 4 was used to prepare the title compound by substituting 3-fluoro-4-methylaniline for 4-chloroaniline in step 3.
  • Step 1 A dry, 2 L, 3-necked, round-bottomed flask was equipped with a mechanical stirrer and addition funnel. To the flask was added 2-thiophenecarboxylic acid (25 g, 195 mmol) in anhydrous THF (500 mL) under argon. The mixture was cooled to -78 0 C with a dry ice-isopropanol bath and allowed to stir for 30 min. n-Butyllithium in Hexanes (2.5 M, 172 mL) was added dropwise over 30 min. The. reaction was kept at -78 0 C for an additional hour with stirring then placed under an atmosphere of dry carbon dioxide. With addition of the carbon dioxide the reaction became thick.
  • the reaction remained at -78 0 C for an additional hour before warming to -10 0 C.
  • the reaction was quenched with 2 N HCl (213 mL) and allowed to reach rt.
  • the layers were separated and the aqueous layer was extracted with EtOAc (3 x 200 mL).
  • the organic layers were combined, dried (Na 2 SO 4 ) and concentrated by rotary evaporation.
  • the brown solid was crystallized from hot isopropanol and dried overnight under vacuum.
  • Step IA Alternatively, 3-thiophenecarboxylic acid rather than 2-thiophenecarboxylic acid has been used in step 1 to yield the same product.
  • Step 2 A lL, round-bottomed flask was equipped with a stir bar and reflux condenser. To the flask was added the product of step 1 (62 g, 360 mmol) in MeOH (500 mL) with a catalytic amount of H 2 SO 4 ( ⁇ 5 mL). The reaction was heated to reflux and stirred for 24 h. The reaction was cooled to rt and concentrated rotary evaporation. The brown mixture was purified by silica gel chromatography (Hexane-EtOAc 80:20 gradient to 60:40).
  • Step 3 A 25OmL, round-bottomed flask was equipped with a stir bar and reflux condenser. To the flask was added the product of step 2 (16 g, 80 mmol), hydrazine hydrate (6.6 mL, 213 mmol), and EtOH (77 mL) and refluxed for 2.5 h. The reaction was cooled to rt and concentrated by rotary evaporation. Water (50 mL) was added and the filtrate was separated from the insoluble solids. The aqueous layer was concentrated by rotary evaporation to give a pale yellow solid. The solid was dried in a vacuum oven overnight at 50 C.
  • Step 4 Preparation of Intermediate B: A 250 mL, round-bottomed flask was equipped with a stir bar and reflux condenser. To the flask was added the product of step 3 (2.5 g, 14.8 mmol), phosphorus oxychloride (45 mL, 481 mmol), and pyridine (4.57 mL, 55 mmol) and refluxed for 2.5 h. The reaction was cooled to rt and poured over ice. The mixture was separated and the aqueous layer was extracted with chloroform (4 x 75 mL). The organic layers were combined, dried (Na 2 SO 4 ) and concentrated by rotary evaporation to give a dark yellow solid.
  • Step 5 A 250 mL, round-bottomed flask was equipped with a stir bar and reflux condenser. To the flask was added the product of step 4 (7.65 g, 37.3 mmol), 4-chloroaniline (4.76, 37.3 mmol) in EtOH (75 mL). The mixture was refluxed for 3 h. An orange solid precipitated from the reaction after 3 h. The reaction was cooled to rt and the solid was collected by filtration and washed with hexane.
  • Step 6 A 150 mL, round-bottomed flask was equipped with a stir bar and reflux condenser. To the flask was added the product of step 5 (0.33 g, 1.1 mmol), 4-pyridylcarbinol (1.2 g, 11.2 mmol) in DBU (2.5 mL, 16.7 mmol) and the mixture was heated to 125 0 C for 24 hours. EtOAc (10 mL) was added to the reaction while hot and then the reaction was poured into water (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 10 mL). The organic layers were combined, dried (MgSO 4 ) and concentrated by rotary evaporation.
  • Step 1 n-Butyllithium (2.5M in hexanes, 196 mL, 491 mmol) was introduced into a dry 3 L 3- necked flask fitted with an addition funnel, argon inlet, and mechanical stirrer. The mixture was diluted with dry THF (500 mL), and cooled to -78 0 C. 3-furoic acid (25 g, 223 mmol) was added as solution in THF (500 mL) dropwise. The mixture was stirred for 1.5 h, at which point dry carbon dioxide was bubbled through the reaction mixture for 1 h. After warming gradually to -10 0 C, the resultant thick white slurry was treated with aqueous HCl (2 N, 446 mL).
  • Step 2 A dry 500 mL round bottomed flask was equipped with a stir bar and an argon inlet. The flask was charged with the crude diacid prepared in Step 1 (44 g) dissolved in MeOH (250 mL). To the reaction mixture was added chlorotrimethylsilane (80 mL, 630 mmol) portionwise. After stirring at room temperature for 15.5 h, the solution was concentrated to an oil and silica (5 g) was added. The mixture was suspended in MeOH (100 mL), and the volatiles were removed. Suspension in MeOH (100 mL) and the removal of the volatiles was repeated an additional two times.
  • Step 3 A 500 mL round bottomed flask fitted with an argon inlet, a reflux condenser, and a stir bar was charged with dimethyl furan-2,3-dicarboxylate (44 g, 236 mmol) dissolved in EtOH (250 mL). Hydrazine hydrate (55 % N 2 H 4 , 40 mL, 3.0 mmol) was added to the solution, and the reaction mixture was warmed to reflux. A yellow solid slowly precipitated over the course of 5.5 h, at which point the mixture was cooled to room temperature. The volatiles were removed under reduced pressure to furnish a yellow paste which was suspended in water and filtered.
  • dimethyl furan-2,3-dicarboxylate 44 g, 236 mmol
  • EtOH 250 mL
  • Hydrazine hydrate 55 % N 2 H 4 , 40 mL, 3.0 mmol
  • Step 4 Preparation of Intermediate C: A l L round bottomed flask was fitted with a reflux condenser, a stir bar, and an argon inlet. The furan from Step 3 (15.5 g, 102 mmol) was added to a mixture of phosphorous oxychloride (300 mL) and pyridine (30 mL), and the resultant orange suspension was warmed to reflux. After heating the reaction mixture for 4 h, the volatiles were removed by rotary evaporation. The residue was poured onto ice, and the aqueous mixture was extracted with CHCl 3 (4 x 250 mL).
  • Step 5 A 100 mL round bottomed flask fitted with a stir bar, an argon inlet, and a reflux condenser was charged with the product of Step 4 (1.50 g, 7.98 mmol) dissolved in ethanol (40 mL). Chloroaniline was added to this mixture (1.02 g, 7.98 mmol), and the resultant suspension was warmed to reflux. After heating for 4 h, the mixture was concentrated by rotary evaporation.
  • Step 6 A 25 mL round bottomed flask was fitted with an argon inlet, a stir bar, and a reflux condenser.
  • the product of step 5 (400 mg, 1.4 mmol) was combined with 4-pyridylcarbinol (782 mg, 7.17 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (2.5 mL 16.7 mmol), and the slurry was warmed to 125 0 C. After stirring for 24, the reaction was cooled, applied directly to the top of a flash column, and eluted with CH 2 Cl 2 ZMeOH 95:5.
  • Steps 5A and 6A Alternatively 4,7-dibromo[2,3- ⁇ /]furopyridazme (Intermediate G below) is used to prepared the title compound by following step 5 but substituting the dibromo intermediate for the dichloro intermediate.
  • Step 6A is conducted by melting the two components together in the presence of CsCO 4 rather than l,8-diazabicyclo[5.4.0]undec-7-ene. The crude product is purified as above.
  • steps 2 to 4 are used by substituting the appropriate heterocycledicarboxylic acid for furan-2,3-dicarboxylic acid to yield the substituted dichloropyridazines D to G found in the below table.
  • the dibromofuropyridazine G was prepared using steps 2-3 from example 9 and then conducting step 4' as follows: to 0.50g (3.287 mmol) of the product of step 3 was added 2.83g (6.57 mmol) of phosphorus pentabromide. This was heated to 125 0 C. At about 115 0 C the reaction mixture melted and then re-solidified before it reached 125 0 C. The reaction mixture was cooled and the solid residue was crushed up and dumped into ice water.
  • Step 1 A stirred solution of ethyl isonicotinate (250 mL, 1.64 mole) and concentrated sulfuric acid (92 mL, 1.64 mole) in N-methylformamide (2.0 L) was cooled to 6°C with an ice bath. Iron (IT) sulfate heptahydrate (22.8 g, 0.0812 mole, milled with a mortar and pestle) was added, followed by the dropwise addition of 30% aqueous hydrogen peroxide (56 mL, 0.492 mole). The additions of iron (H) sulfate and hydrogen peroxide were repeated four additional times, while the reaction temperature was kept below 22°C.
  • Example 8 A 25 mL, 3-necked, round-bottomed flask was equipped with a stir bar and thermometer. To the flask was added the product of Example 8 (0.475 g, 1.29 mmol), iron sulfate heptahydrate (0.179 g, 0.64 mmol), formamide (11.15 mL, 281 mmol) and cone. H 2 SO 4 (0.14 mL). The mixture was stirred for 30 min at rt at which time H 2 O 2 (0.2 mL, 6.44 mmol) was added drop wise to the mixture. The reaction stirred at room temperature for an additional hour and then heated to 55 0 C over 30 min. The reaction was kept at this temperature for 3 h and then cooled to rt.
  • Example 10 The procedure used for the preparation of Example 10 was used to prepare the title compound by substituting the product of example 4 for the product of example 8.
  • the crude product was purified by preparative TLC plate (1 :4 v/v hexane-ethyl acetate, 19 % yield) of the title compound as a yellow solid.
  • Example 11 The procedure used for the preparation of Example 11 was used to prepare the title compound by substituting the product of example 4 for the product of Example 8. The crude product was purified by column chromatography (2:3 v/v hexane-ethyl acetate, 20 % yield) of the title compound as a yellow solid.
  • the reaction mixture was cooled with an ice bath.
  • a solution of sodium citrate 600 mL, IM, 600 mmol was added under vigorous stirring.
  • the resulting suspension was stirred vigorously for additional 10 min.
  • the solid was collected by filtration, washed with water (3x100 mL), and dried under vacuum at 50 0 C for 16 hours.
  • the crude product (21 g) was purified by filtering through a silica gel pad eluting with 5% CH 3 OHZCH 2 Cl 2 .
  • the resulting 3.7 g product was recrystallized in CH 3 CN (125mL, boiled for 1.5 hours).
  • the solid was collected by filtration, washed with CH 3 CN (2x15mL), and dried under vacuum at 50 0 C for 16 hours.
  • Example 14A Preparation of 4-(4-chlorophenylamino)-7-(2-methylaminocarbonyl-4- pyridylmethoxy)furo-[2,3-d]pyridazine - Process 2
  • step 5 To a mixture of the Intermediate from Example 9, step 5 (10.0 g, 35.7 mmol), Intermediate H (12.4 g, 74.6 mmol), and 18-crown-6 (0.42 g, 1.59 mmol) in toluene (100 mL) was added KOH powder
  • Example 14 The procedure used for the preparation of Example 14 was used to prepare the title compound by substituting Formamide for N-methylformamide.
  • the reaction was conducted with 500 mg of final product from Example 9 and proportional amounts of solvents and reagents.
  • the crude product was purified by HPLC on a 75x30 mm Cl 8 column and a linear gradient elution from 10 to 100% acetonitrile in water with 0.1% trifluoroacetic acid at 10 ml/min. over 10 min. to yield 18 mg of the title compound as a yellow solid: HPLC (50x4.6 mm YMC CombiScreen® Cl 8 column, linear gradient 10 to 100% acetonitrile in water with 0.1% trifluoroacetic acid at 3 ml/min. over 5 min., UV detection at 254 nm) 2.35 min. peak; MS ES 396 (M+H) + .
  • step 4 (1.00 g, 4.90 mmol) was added />-chloroaniline (622 mg, 4.90 mmol) and absolute ethyl alcohol (10.0 mL). The mixture was refluxed at 95°C for 2 hrs and then cooled to room temperature. The yellow precipitate (2) that formed was filtered and washed with isopropyl alcohol, 4.0 N KOH, H 2 O, and then hexane. The filtrate (2) was then mixed 6- aminobenzothiazole (883 mg, 5.88 mmol) in 10 mL of n-butanol, and heated at 150 0 C overnight. The reaction was allowed to cool to room temperature before the solvent was removed by rotary evaporation.
  • Example 17 The procedure used for the preparation of Example 17 was used to prepare the title compound by substituting 5-aminoindane for 4-chloroaniline.
  • the crude product was purified by flash chromatography on silica gel using 30% ethyl acetate/hexane as the eluent.
  • Example 16 The procedure used for the preparation of Example 16 was used to prepare the title compound by substituting the product of Example 21 for the product from Example 9. The reaction was conducted with 250 mg of the starting material and proportional amounts of solvents and reagents. The crude product was purified by HPLC on a 75x30 mm Cl 8 column and a linear gradient elution from 10 to 100% acetonitrile in water with 0.1% trifluoroacetic acid at 10 ml/min. over 10 min. to yield 16 mg of the title compound as a yellow solid: HPLC (50x4.6 mm YMC CombiScreen® C18 column, linear gradient 10 to 100% acetonitrile in water with 0.1% trifluoroacetic acid at 3 ml/min. over 5 min., UV detection at 254 nm) 1.98 min. peak; MS ES 392 (M+H) + . Examples 23 - 80: Preparation of Invention Compounds by Methods A-I ,A-2 and A-3
  • Method A-I Equal equivalents of dichloride (1) and M-NH 2 are refluxed in the appropriate amount of absolute ethanol at 95 0 C for 2 hrs. The reaction mixture is allowed to cool to room temperature and the precipitate (2) that forms is filtered and washed sequentially with isopropyl alcohol, 4.0 N KOH, H 2 O, and hexane, and then dried. The filtrate (2) is then reacted with 1.2 equivalent Of Q-NH 2 in an appropriate amount of n-butyl alcohol at 150 0 C for 10 hrs. The reaction is cooled to room temperature before the solvent is evaporated under reduced pressure. The residue is treated with aqueous 4.0 NKOH solution and extracted with dichloromethane.
  • Method A-2 One equivalent of dichloride (1) and 2.2 equivalent of M-NH 2 are refluxed in an appropriate amount of n-butanol at 150 0 C for 10 hrs. The reaction mixture is allowed to cool to room temperature and the precipitate (4) that forms is filtered and washed sequentially with isopropyl alcohol, 4.0 NKOH, H 2 O, and hexane, and then dried. The crude product (4) is purified by preparative TLC or flash chromatography on silica gel using dichloromethane/methanol (95:5) as the eluent. Final product is confirmed by LC/MS and/or ⁇ MR. The invention compounds of Examples 26 - 33 and 75 as shown in the below table were prepared by method A-2.
  • Method A-3 One equivalent of dichloride (1) and one equivalent of M-NH 2 are suspended in DME (0.3M) and water is added until a solution was formed. The reaction mixture is heated to 65 0 C for 48 h. After cooling to rt, the resulting precipitate is filtered and washed with DME to provide the intermediate product (2) which is confirmed by LC/MS and NMR. In some instances, intermediate (2) is further purified by preparative TLC or washed with other solvents. A suspension of (2) (1 equiv), carbinol (3) (3 equiv), and 18-crown-6 (10 mol %) in toluene (0.3M) is stirred at rt for 10 min.
  • HPLC ES-MS HPLC - positive ion electrospray mass spectroscopy
  • TLC silica gel plates
  • R/ values and solvents are shown.
  • HPLC retention times are given for other examples in this table; a HPLC - electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a YMC Pro Cl 8 2.0 mm x 23 mm column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization.
  • Method B-I Dibromoisoquinoline (5, 29 mg, 0.1 mmol)
  • Example 1, step 1, and M-NH 2 (0.2 mmol) in 8-mL vial were heated in 1 mL of n-butanol at 90 0 C for 36 hrs. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. 4-Mercaptopyridine (23 mg, 0.2 mmol) and cesium carbonate (67 mg, 0.2 mmol) were added to the vial. The mixture was heated at 180 0 C for 1 hr and was allowed to cool to room temperature. Methanol (2 mL) was added to the vial and the mixture was sonicated for 10 min and filtered.
  • HPLC - electrospray mass spectra were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a YMC Pro Cl 8 2.0 mm x 23 mm column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Gradient elution from 90% A to 95% B over 4 minutes was used on the HPLC. Buffer A was 98% water, 2% Acetonitrile and 0.02% TFA. Buffer B was 98% Acetonitrile, 2% water and 0.018% TFA. Spectra were scanned from 140-1200 amu using a variable ion time according to the number of ions in the source. Examples 93 - 105: Preparation of Novel Phthalazine Invention Compounds by Parallel Synthesis
  • Method A-I or A-2 were used to prepare the novel phthalimide invention compounds 93 - 105 from 1 ,4-dichlorophthalazine (for preparation see Novartis patent WO98/35958, 11.02.98) rather than the dichloroheterocyclopyridazines together with the appropriate bicyclic and substituted anilines.
  • HPLC - electrospray mass spectra were obtained using a Hewlett-Packard 1100 HPLC equipped with a quaternary pump, a variable wavelength detector, a YMC Pro Cl 8 2.0 mm x 23 mm column , and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Gradient elution from 90% A to 95% B over 4 minutes was used on the HPLC. Buffer A was 98% water, 2% Acetonitrile and 0.02% TFA. Buffer B was 98% Acetonitrile, 2% water and 0.018% TFA. Spectra were scanned from 140-1200 amu using a variable ion time according to the number of ions in the source. Examples 106 - 114: Preparation of Salts of Example 14.
  • Example 14 The product of Example 14 (1.50 g, 3.66 mmol) was stirred as a slurry in methanol (20 ml) as a solution of toluenesulfonic acid hydrate (0.701 g, 3.67 mmol) in methanol (5 ml plus 5 ml rinse) was added quickly dropwise. All materials dissolved over 5 min to yield a yellow solution. Anhydrous ether (30 ml) was added and stirring was continued for 5 minutes until solid began to precipitate.
  • Example 104 The resultant mixture was chilled with stirring in an ice/water bath for 45 minutes and then the solid title product (Example 104) was collected by filtration, washed with ether and dried at 55 0 C in a vacuum oven until NMR analysis showed a lack of solvents (1.5 hours).
  • Other compounds were prepared in a similar way by using a variety of acids rather than toluenesulfonic acid. Scale up and use of less methanol in the first step generally led to quicker precipitation of salts and a variety of solvents were used rather than ether, as indicated, to help crystalize the individual salts. In some cases the methanol was first removed by evaporation in vacuo. Final drying took between 1.5 hours and several days, depending on the quantity of material and the specific specific acid used.
  • KH Krebs-Henseleit
  • segment contractility is then tested by an initial exposure to a high K + solution (120 mmol/1 K + - KH solution, which is identical to KH solution except that NaCl is replaced by KCl on an equimolar basis).
  • the vessels are than pre-contracted using K + (50 mmol/1) KH solution.
  • K + (50 mmol/1) KH solution When the contraction is stabilized, an accumulative dose response curve of the compound/combination tested is constructed.
  • the stabilized contraction induced by K + (50 mmol/1) KH solution is defined as 100% tension.
  • the relaxation is expressed as percentage tension.
  • the mentioned monocrotaline (MCT) treated rats are randomized to receive example 14 [4-(4-chlorophenylamino)-7-(2-methylaminocarbonyl-4-pyridylmethoxy)furo-[2,3-d]pyridazine] 10 mg/kg or vehicle by gavage once daily after the onset of moderate pulmonary arterial hypertension starting 14 days after the injection of MCT until the final hemodynamic measurement on day 28.
  • animals with MCT induced pulmonary arterial hypertension treatment with example 14 markedly decreases right ventricular systolic pressure, compared to vehicle treated animals (control: 25 ⁇ 0,56 mmHg; example 14: 42,04 ⁇ 3,21 mmHg vs.
  • placebo 71,02 ⁇ 5,38 mmHg (mean ⁇ SEM).
  • This effect of example 14 is paralleled by an inhibition of right ventricular hypertrophy (right ventricle/left ventricle +septum ratio control: 0,26 ⁇ 0,01; example 14: 0,32 ⁇ 0,02 vs. placebo: 0,54 ⁇ 0,04).

Abstract

La présente invention concerne des compositions pharmaceutiques et des combinaisons pour traiter, prévenir ou prendre en charge une hypertension pulmonaire comportant des produits pharmaceutiques à petites molécules hétérocycliques, et plus particulièrement, des pyridines et des pyridazines substituées combinées facultativement avec au moins un agent thérapeutique supplémentaire.
PCT/EP2007/002985 2006-04-15 2007-04-03 Composés pour traiter une hypertension pulmonaire WO2007118602A1 (fr)

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US12/297,217 US8304406B2 (en) 2006-04-15 2007-04-03 Compounds for treating pulmonary hypertension
EP07723926A EP2010173A1 (fr) 2006-04-15 2007-04-03 Composés pour traiter une hypertension pulmonaire
JP2009505742A JP2009533479A (ja) 2006-04-15 2007-04-03 肺高血圧症処置用化合物
CA002648957A CA2648957A1 (fr) 2006-04-15 2007-04-03 Composes pour traiter une hypertension pulmonaire

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CN105294686A (zh) * 2015-11-30 2016-02-03 郑州大明药物科技有限公司 一种利奥西呱的制备方法
CN107129502A (zh) * 2017-04-13 2017-09-05 亿腾药业（泰州）有限公司 EOC315 Mod.I晶型化合物及其制备方法
WO2018080216A1 (fr) * 2016-10-28 2018-05-03 Daewoong Pharmaceutical Co., Ltd. Dérivé de phénylphtalazine, sa méthode de préparation et composition pharmaceutique le comprenant
CN109232546A (zh) * 2018-09-25 2019-01-18 中国人民解放军总医院 一种嘧啶磺酰胺类衍生物的医药用途
WO2023283080A1 (fr) 2021-07-07 2023-01-12 Teva Pharmaceuticals International Gmbh Formes à l'état solide de 4-[[4-(4-chloroanilino)furo[2,3-d]pyridazin-7-yl]oxyméthyl]-n-méthylpyridine-2-carboxamide et leur sel

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MX2015005812A (es) 2012-11-08 2015-09-23 Pfizer Compuestos heteroaromaticos y su uso como ligandos de dopamina d1.
EP3082428A4 (fr) 2013-12-09 2017-08-02 Respira Therapeutics, Inc. Formulations en poudre d'inhibiteur pde5 et procédés y associés
AU2021206203A1 (en) * 2020-01-07 2022-08-18 Shanghai Huayu Biotechnology Co., Ltd. Combination cancer therapy using CHK inhibitor

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CN105294686A (zh) * 2015-11-30 2016-02-03 郑州大明药物科技有限公司 一种利奥西呱的制备方法
WO2018080216A1 (fr) * 2016-10-28 2018-05-03 Daewoong Pharmaceutical Co., Ltd. Dérivé de phénylphtalazine, sa méthode de préparation et composition pharmaceutique le comprenant
US10947241B2 (en) 2016-10-28 2021-03-16 Seoul National University Hospital Phenyl phthalazine derivative, method for the preparation thereof, and pharmaceutical composition comprising the same
CN107129502A (zh) * 2017-04-13 2017-09-05 亿腾药业（泰州）有限公司 EOC315 Mod.I晶型化合物及其制备方法
CN110520425A (zh) * 2017-04-13 2019-11-29 泰州亿腾景昂药业有限公司 EOC315 Mod.I晶型化合物及其制备方法
US10954246B2 (en) 2017-04-13 2021-03-23 Taizhou Eoc Pharma Co., Ltd. Compound of EOC315 Mod.I crystal form and preparation method thereof
CN110520425B (zh) * 2017-04-13 2023-04-14 泰州亿腾景昂药业股份有限公司 EOC315 Mod.I晶型化合物及其制备方法
CN109232546A (zh) * 2018-09-25 2019-01-18 中国人民解放军总医院 一种嘧啶磺酰胺类衍生物的医药用途
WO2023283080A1 (fr) 2021-07-07 2023-01-12 Teva Pharmaceuticals International Gmbh Formes à l'état solide de 4-[[4-(4-chloroanilino)furo[2,3-d]pyridazin-7-yl]oxyméthyl]-n-méthylpyridine-2-carboxamide et leur sel

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US8304406B2 (en) 2012-11-06
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